This invention relates generally to the diagnostic testing of biological fluids and, more particularly, to the calibrating of sensors used in such testing.
Low-cost, disposable, electrochemical electrode assemblies have special utility as part of infusion fluid delivery systems commonly used in hospital patient care. Such systems infuse nutrients, medications, and the like directly into the patient at a controlled rate and in precise quantities, for maximum effectiveness. Such infusion fluid delivery systems are connected to a patient via an intravenous (IV) port, in which a hollow needle/catheter assembly is inserted into a blood vessel of the patient and thereafter an infusion fluid is introduced into the vessel at a controlled rate, typically using a peristaltic pump. Blood chemistry monitoring systems that are combined with infusion fluid delivery systems of this kind use the IV port to periodically withdraw a blood sample into an electrode assembly, perform measurements of blood ion concentrations and the like, and then discard the blood or reinfuse it into the patient. The system then resumes delivery of the infusion fluid.
The electrode assembly typically includes a reference electrode and a plurality of sensing electrodes, or sensors, that are each sensitive to a particular ion or species of interest. All of the electrodes are typically embedded in the base of the electrode assembly. For example, ion-selective electrodes generate electrical signals only in response to contact with the particular ion to which they are sensitive, and therefore provide selective measurement of the amount of that ion in the blood. This type of sensing electrode can be provided to measure, for example, blood calcium, hydrogen ion (i.e., pH), chloride, potassium, and sodium. In a differential measurement system, the reference electrode might be another ion-selective electrode (e.g., a chloride or sodium electrode) that is continuously exposed to a calibration or reference fluid. Alternatively, in a non-differential measurement system, a conventional reference electrode (which maintains a fixed potential when exposed either to reference fluid or to analyte) is required.
Presently employed electrochemical sensors for clinical diagnostic applications fall into three categories: ac impedance sensors, amperometric sensors, and potentiometric sensors.
An example of an ac impedance-type sensor is an hematocrit (Hct) sensor. Hematocrit is defined as the volume percent of red cells in the blood. Hematocrit can be determined by measuring the blood's ac impedance, using a pair of metal electrodes, typically at 1 kiloHertz (kHz).
An amperometric sensor produces an electrical current that varies with the concentration of a specific component of interest. For example, oxygen partial pressure (pO.sub.2) and glucose (Glu) are commonly determined using amperometric sensors. An oxygen sensor assembly usually includes a working electrode formed from a noble metal, e.g., platinum or gold, and a suitable counter electrode formed of a different metal, e.g., silver/silver chloride. An oxygen-permeable, but liquid-impermeable, membrane is usually mounted over the sensor assembly, to separate the sample from the internal electrolyte and thereby avoid contamination. The sensor measures the limiting current of oxygen reduction at the working electrode according to the following equation: EQU O.sub.2 +2H.sub.2 O+4e.fwdarw.4OH.sup.-
This accomplished by applying a bias voltage of approximately 700 mV between the working (negative) electrode and the counter (positive) electrode. The resulting current is proportional to the pO.sub.2 level in the sample.
The glucose sensor is very similar in construction to the oxygen sensor. One difference is that a hydrophilic membrane with immobilized glucose oxidase (i.e., GOD) is used instead of the hydrophobic oxygen membrane. In the presence of glucose oxidase, the following reaction occurs: EQU Glucose+O.sub.2 GOD.fwdarw.Gluconic Acid+H.sub.2 O.sub.2
In this case, glucose concentration can be determined by polarizing the working electrode either anodically or cathodically by approximately 700 mV, to measure the rate of hydrogen peroxide oxidation or oxygen reduction.
A potentiometric sensor produces an electrical voltage that varies with the species of interest. Ionic species, such as hydrogen ion (H.sup.+), sodium (Na.sup.+), potassium (K.sup.+), ionized calcium (Ca.sup.++) and chloride (Cl.sup.-), are commonly measured by ion-selective electrodes, a typical class of potentiometric sensors.
The commonly used CO.sub.2 sensor, sometimes known as the Severinghaus electrode, also is a potentiometric sensor (and is, in fact, essentially a modified pH sensor). Typically, it consists of a pH electrode and a reference electrode, with both covered by a hydrophobic, gas-permeable/liquid-impermeable membrane such as silicone. A thin layer of weakly buffered internal electrolyte. e.g., 0.001 M NaHCO.sub.3, is located between the hydrophobic membrane and the pH sensing membrane. Carbon dioxide in the sample eventually reaches equilibrium with the internal electrolyte, and it produces a pH shift according to the following equation: EQU CO.sub.2 +H.sub.2 O.fwdarw.H.sup.+ +HCO.sub.3
The resulting pH shift is then measured by the pH electrode. Therefore, a direct relationship exists between a sample's CO.sub.2 partial pressure (pCO.sub.2) and its pH.
The accuracy of measurement obtained with any of the above-described sensors can be adversely affected by drift, particularly after exposure to biological fluids such as whole blood. Frequent calibration is therefore required. This is particularly true for gases such as pO.sub.2 and pCO.sub.2, because any change in the gas transport properties of the membrane can affect the sensor output.
To this end, a number of calibration fluids are usually needed. This is because at least two different calibrant concentration levels are usually required to characterize a sensor. For a multi-parameter system, it is sometimes impossible to use the same two solutions to calibrate all of the sensors, due to concerns such as chemical incompatibility and long term stability. Moreover, since it is technically difficult to maintain pCO.sub.2 and pO.sub.2 constant at desired calibration levels, most conventional blood chemistry analyzers carry two gas cylinders and several bottles of reagents just to fulfill the calibration requirements. This makes the analyzers bulky and cumbersome to use.
Attempts have been made to fill pre-tonometered liquid calibrants sealed into aluminum foil pouches under partial vacuum, as described in U.S. Pat. No. 4,734,184 to Burleigh. This approach has substantially reduced the blood chemistry analyzer's size and has improved the analyzer's portability. However, the contents of the pouch have a limited life after the pouch has been opened.
The current trend has been to move away from bench top analyzers toward the use of bedside analyzers. Moreover, instead of taking samples from the patients, sensors either are miniaturized and inserted into a blood vessel (in vivo) or are constructed as part of a flow cell connected to the patient end of an existing vascular access port (ex vivo), to provide continuous monitoring of blood chemistry.
The in vivo approach is conceptually more attractive, because it provides continuous results without intervention. However, it is considered more difficult to implement in practice, one major difficulty being blood clotting. Blood compatibility also has been a challenging issue. Even with a short term solution in hand, once sensors have been placed in the blood stream, repeated calibration becomes very difficult.
The ex vivo approach, originally described in U.S. Pat. No. 4,573,968 to Parker, employs a control unit to periodically draw a small amount of blood into contact with sensors that are incorporated into an in-line flow cell. After a measurement has been taken, the control unit resumes delivering physiological saline into the blood vessel. As a result, the blood drawn is effectively flushed back into the patient and the sensors are washed clean. U.S. Pat. No. 4,535,786 to Kater discloses a method to use an infusible IV saline solution to calibrate ionic species in the biological fluid. However, Kater fails to address the calibration of species such as pO.sub.2 and pCO.sub.2.
As mentioned above, blood chemistry sensors ordinarily require frequent calibration to maintain the accuracy of measurement. The calibration of pH and pCO.sub.2 sensors remains a particular challenge. In aqueous solutions, these two parameters are inter-related by the following equation: EQU CO.sub.2 +H.sub.2 O.fwdarw.H.sup.+ +HCO.sub.3.sup.-
At 37.degree. C., the pH in a simple bicarbonate-containing physiological saline solution equal to: EQU 6.10+log ([HCO.sub.3.sup.-]/ 0.0301pCO.sub.2)
Since the normal pCO.sub.2 in arterial blood is approximately 40 mmHg, while the atmosphere contains 0.2-0.5 mmHg of CO.sub.2, atmospheric CO.sub.2 levels are not only too low, but they are also too variable to serve as a calibration point. An external CO.sub.2 source is therefore required. Normally, the approach used in the art is to tonometer the solution with a known CO.sub.2 -containing gas and to then package the gas-equilibrated solution in a sealed container. This approach not only is costly, but also requires considerable effort to demonstrate that the solution can be safely infused.
U.S. Pat. No. 4,736,748 to Nakamura suggests that simultaneous calibration for Na.sup.+, K.sup.+, Ca.sup.++, glucose, and hematocrit can be carried out using Lactated Ringer's solution with added glucose. However, such a solution could not be used for pH, pCO.sub.2 and/or pO.sub.2 calibration, because the solution has no well defined pH value or pO.sub.2 value, and it contains essentially no CO.sub.2. Indeed, since the amount of oxygen dissolved in Lactated Ringer's solution is not fixed (being a function of ambient temperature and barometric pressure--parameters which Nakamura does not contemplate monitoring), the patent fails to teach how to use the solution as an oxygen calibrant.
While the Burleigh patent identified above describes a solution that can be used for calibrating CO.sub.2, the solution does not appear to be infusible. The patent fails to provide any guidance as to suitable calibration solutions for use with combined infusion fluid delivery/blood chemistry measurement system.
U.S. Pat. No. 5,132,000 to Sone et al. is similar to the Burleigh patent, in that it describes solutions that can be used for calibrating CO.sub.2 -containing solutions. However, the solutions do not appear to be infusible.
U.S. Pat. No. 5,505,828 to Wong et al. describes a calibration solution that is useful for calibrating an array of sensors capable of simultaneously measuring several blood chemistry parameters, including pCO.sub.2 and pO.sub.2, pH, sodium, potassium, ionized calcium, ionized magnesium, chloride, glucose, lactate, and hematocrit. Moreover, the solution is infusible, whereby it can facilitate calibration on a regular basis of all the sensors in the array, which is in constant fluid communication with the body.
The Wong et al. calibration solution works well for periods of time of up to about 8 hours. However, over longer periods of time, e.g., 12-24 hours, the solution's pH value will rise excessively, and its corresponding pCO.sub.2 will drop excessively. This is due primarily to the diffusion of CO.sub.2 from the infusion bag that initially carries the solution and from the IV set that carries the solution from the infusion bag to the sensor array. This variation in concentration can lead to significant calibration errors.
The Wong et al. calibration solution can function satisfactorily to calibrate pO.sub.2, because concentration of O.sub.2 in the solution is substantially the same as the concentration of O.sub.2 in the atmosphere and because O.sub.2 therefore will not diffuse from the infusion bag or the IV set. However, the amount of dissolved O.sub.2 in the solution varies inversely with the solution's temperature. Consequently, if the solution delivered to the sensor array undergoes a sudden and significant temperature change, some of the dissolved O.sub.2 will come out of solution and calibration errors can arise.
It should, therefore, be appreciated that there is a need for an improved method of calibrating sensors capable of measuring several blood chemistry parameters, including pH, pCO.sub.2 and O.sub.2, which can accommodate variations in the pCO.sub.2 of a calibration solution due to diffusion of CO.sub.2 from the solution's container, and which can accommodate significant variations in the temperature of the solution delivered to the sensors. The present invention fulfills this need.